Painful neuropathy is the principal dose-limiting factor in chemotherapy with vincristine, taxol and cisplatin and often forces patients to withdrawal from what could otherwise be curative therapy. Moreover, chemotherapy-induced pain is refractory to treatment and often persists in cancer survivors producing prolonged disability and suffering. In that these drugs are the treatment of choice for a multitude of lymphoid and solid tumors, hundreds of thousands of patients each year are affected by this neuropathy. The long-term goal of this project is to determine the mechanism of chemotherapy-induced pain and identify potential therapeutic interventions for its relief and prevention. Here we propose to test two hypotheses related to this goal in two specific aims in complementary studies in humans who are undergoing chemotherapy with taxol or cisplatin. Hypothesis 1: Chemotherapy induces neuropathic pain due to a preferential impairment of myelinated primary afferent fiber function. Specific Aim 1: Quantitative sensory testing will be used to define primary afferent function at three week intervals in patients as they undergo chemotherapy for non-small cell lung cancer and breast cancer. The results in patients who develop pain will be contrasted with those in normal volunteers and with data from patients who do not develop pain. Hypothesis 2: The onset of chemotherapy induced pain is associated with increases in serum cytokine levels. Specific Aim 2: Blood serum levels of cytokines will be measured at the same intervals as above in patients as they undergo chemotherapy for lung and breast cancer. The results in patients who develop pain will be contrasted with that in patients who do not develop pain. In summary this project will yield insight to the mechanisms of chemotherapy-induced pain, the major dose limiting side effect of front-line chemotherapeutic drugs. Success in this project will result in the identification of near-term treatment candidates for evaluation in a larger more in-depth proposal that has the potential to impact on the survival, quality of life and return to productivity of cancer survivors.